Synthesis and crystal structure of a bench-stable pyridinium ketene hemiaminal: 1-(1-ethoxyethenyl)-2-[methyl(phenyl)amino]pyridin-1-ium trifluoromethanesulfonate

The N-quaternized ketene N,O-acetal, 1-(1-ethoxyvinyl)-2-(methyl(phenyl)amino)pyridin-1-ium trifluoromethanesulfonate was synthesized and its structure determined, making it a rare example of this class of compounds to be structurally characterized.


Chemical context
N-Quaternized ketene N,O-acetals are a generally unstable class of compounds, most often invoked as reactive intermediates (Kantlehner, 2006). Consequently, there are very few reports of isolable and well-characterized compounds in this class despite their first appearance in the literature over eight decades ago (Arens et al., 1955;Barnes et al., 1940;Filippova et al., 1983;Herkes & Simmons, 1973;Klages & Drerup, 1941;Lehn & Seher, 1966;Otsuru et al., 1969). In 2018, our laboratory discovered that several pyridinium ketene hemiaminals were unusually stable analogues of the N-quaternized ketene N,O-acetal class, amenable to isolation and purification by chromatography or recrystallization (Fig. 1, compounds I-III) (Shapiro et al., 2018). An ensuing report expanded access to over forty bench-stable examples of this rare class of compounds (McConnell et al., 2021). However, to date there has been only one published X-ray crystal structure (Fig. 1, compound I) of these unusual unsubstituted ketene hemiaminals.
Pyridinium ketene hemiaminals are an emerging class of reagents in organic synthesis that are able to engage in a variety of reaction modes such as electrophilic aromatic substitutions, nucleophilic aromatic substitutions (S N Ar), and amidations (Shapiro et al., 2018;McConnell et al., 2021). As part of our ongoing efforts to explore the use of these compounds in valuable synthetic applications, we have sought to employ 2-halopyridinium ketene hemiaminals as facile electrophiles in mild S N Ar reactions with amine nucleophiles, en route to the bioactive 2-aminopyridine products such as IV (Fig. 1). During the course of this study, 2-aminopyridium ketene hemiaminal IV yielded high-quality crystals. Given the scarcity of X-ray analyses on this compound class, we were compelled to investigate the X-ray structure of IV in depth.

Structural commentary
The substituted pyridinium cation of the title compound is built from three individually planar fragments connected to form a non-coplanar molecule (Fig. 2). The 2-(methylamino)pyridine fragment forms one plane (A), the phenyl group extending from the amino-nitrogen atom forms a second plane (B), and the ethoxyvinyl substituent extending from the pyridine-nitrogen atom forms a third plane (C). Mean plane to mean plane angles between the fragments are 71.71 (4) between A and B, 68.16 (4) between A and C, and 29.77 (6) between B and C. The phenyl group attached to the amino-nitrogen atom is folded toward the same side of the aminopyridine fragment as the ethoxyvinyl substituent, likely requiring their mean plane to mean plane angles to be closest to parallel. The orientation of the ethoxyvinyl substituent on the pyridine ring [C1-N1-C6-O1 torsion angle of 116.44 (12) ] is similar to that in the 2-chloro-substituted compound I, CSD refcode JETTOU, which has a mean plane to mean plane angle between the pyridine and ethoxyvinyl fragments of 70.2 (2) and a C-N-C-O torsion angle of 109.1 (2) about the exocyclic N-C bond, which was shown to be an energetically favorable arrangement (Shapiro et al., 2018).

Supramolecular features
The triflate anions and substituted pyridinium cations are arranged in individual columns along the c-axis of the unit cell, and pack in alternating fashion along the a-and b-axes of the unit cell (Fig. 3). All three oxygen atoms of the triflate anion Structure and atomic numbering scheme of the title compound, shown as 50% probability ellipsoids.
act as acceptor atoms for C-HÁ Á ÁO interactions from the cation ( Table 1). As a result, there are six C-HÁ Á ÁO interactions between a central cation and four neighboring triflate anions where HÁ Á ÁO is less than 2.60 Å (Fig. 4). The six contacts originate from the pyridinium fragment (two), methyl group on the amino nitrogen atom (two), vinyl carbon atom (one), and ethoxy group (one). The shortest contact occurs from C5 on the pyridinium ring, with HÁ Á ÁO = 2.25 Å and CÁ Á ÁO = 3.1819 (16) Å . Collectively, the six C-HÁ Á ÁO interactions create a two-dimensional slab in the bc plane. These slabs may be considered to extend into a three-dimensional framework if a short C-HÁ Á ÁF contact [HÁ Á ÁF = 2.44 Å , CÁ Á ÁF = 3.324 (2) Å , C-HÁ Á ÁF = 153.1 ] is considered from the C13 atom of the phenyl fragment to the F2 atom of the anion. Only one such contact occurs to the CF 3 side of the anions.

Database survey
A CSD search revealed only six hits for any pyridinium-1vinyl-1-ether fragment (CSD Version 5.43, Update 4, November 2022; Groom et al., 2016). Of these, five were of substituted isoquinolinium salts, where the vinyl group of the searched fragment corresponds to a C C bond in a thiazole ring fused to the substituted isoquinoline, making them largely unrelated to the title compound (Matsumoto et al., 2018(Matsumoto et al., , 2022. The remaining hit is the related compound and precursor material, I, 2-chloro-1-(1-ethyoxyethenyl)pyridin-1ium trifluoromethanesulfonate, CSD refcode JETTOU (Shapiro et al., 2018). Expansion of the search to include pyrazinium-or pyrimidinium-based fragments produced no hits.

Synthesis and crystallization
A sealed 0.5-2.0 mL Biotage microwave vial was charged with potassium carbonate (69 mg, 0.5 mmol), freshly prepared 2-chloropyridinium ketene hemiaminal I (167 mg, 0.5 mmol) (McConnell et al., 2021) and dichloromethane (1 mL). While stirring the resulting suspension at room temperature, N-methylaniline (0.054 mL, 0.5 mmol) was slowly added. After one minute of stirring at room temperature, the sealed microwave vial was placed in a pre-heated 313 K oil bath and stirred for 24 h. The reaction mixture was cooled to room temperature then concentrated to a residue that was purified by silica gel column chromatography using a 0-70% gradient of isopropanol in chloroform to provide compound IV as a yellow solid (190 mg, 94%

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.